It is now apparent that the shuttling of lactate through the interstitium and vasculature provides a major means of distributing carbohydrate potential energy during exercise. To further explore aspects of the 'lactate shuttle' hypothesis, two aims are identified. Under the umbrella of Aim 1, we will address a set of interrelated goals, all directed to understanding regulation of substrate supply during exercise. Under Aim 1a, we will evaluate the hypothesis that endurance training enhances lactate clearance during exercise. Under Aim 1b, we will address the hypothesis that sympatho-adrenal responses, specifically epinephrine, act to stimulate glycogenolysis in 'active' (contracting) muscles as well as 'inactive' (non-contracting) muscles and, thereby, provide for feed- forward regulation of lactate supply during exercise. Under Aim 1c, we will develop and test a model of lactate uptake and release during exercise. To explore aspects of substrate utilization during exercise, we will use combinations of tracer and non-tracer lactate infusion (ie., the 'lactate clamp'), gluconeogenic blockade (with 3-MPA), beta2-adrenergic blockade (with ICI 118,551), glucose clamping (with and without somatostatin), and epinephrine infusion. Additionally, tail suspension of rats during treadmill running to produce active (fore limb) and inactive (hind limb) muscle beds will be used to verify that endocrine signals are responsible for mobilization of glycogen and lactate release from inactive muscle beds during contraction in other muscle beds. By these means we hope to elucidate the hormonal and substrate signals coordinating the 'shuttle' mechanism. Under Aim 2 we will address the hypothesis that a muscle cell membrane lactate transport protein (permease) exists and that presence of such a permease facilitates function of the 'lactate shuttle.' Specifically, we propose to isolate and purify the sarcolemmal lactate transport protein, as well as describe the regulation of protein induction in different muscle fiber types, and in response to exercise training.